Eukaryotic DNA is packaged into chromatin, and this chromatin has a well-defined organization. Chromatin is composed of nucleosome building blocks, whose positioning along the DNA dictates the accessibility of gene regulatory elements, and ultimately the expression levels of genes. Nucleosomes are highly regulated through many mechanisms including: post-translational modifications, deposition and eviction that is facilitated by chaperones, and re-positioning facilitated by chromatin remodeling complexes. Such nucleosome states further regulate gene expression by interacting with specific gene regulatory proteins. How nucleosome states interface with gene regulatory factors is largely unknown and is central to our understanding of how gene expression is controlled and mis-regulated in diseases. Here, we propose to further our understanding of this interface by first mapping the genomic position of individual nucleosome states at high resolution as model gene expression programs (heat shock and sporulation) unfold. Examples of nucleosome states include histone modifications, and nucleosome phasing, positioning, and width. Second, we will ascertain the contribution of such states to chromatin organization and gene expression, by examining what fails to happen when such states are eliminated through mutagenesis. Third, we will create high-resolution genome-wide maps of nucleosomes that interact with specific chromatin and gene regulatory factors.
These aims are intended to first describe the landscape of nucleosomal states at high resolution, then identify their function, and then ascertain their interplay with gene regulatory factors using primarily Saccharomyces as a model system.Key nucleosomal patterns will be further explored in metazoan model systems, to ascertain whether such patterns represent fundamental principles in eukaryotes.
Since nucleosome positioning and regulation play central roles in controlling gene expression from yeast to man, and gene expression is the origin of both normal and diseased cellular behavior, knowledge of the genomic organizational state of nucleosomes is key toward maintaining proper cell physiology and rectifying aberrant states. This project is intended to provide a greater understanding of nucleosomal states in relation to gene expression.
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